Role for Mitochondrial Reactive Oxygen Species in Brain Lipid Sensing

Abstract

The ability for the brain to sense peripheral fuel availability is mainly accomplished within the hypothalamus, which detects ongoing systemic nutrients and adjusts food intake and peripheral metabolism as needed. Here, we hypothesized that mitochondrial reactive oxygen species (ROS) could trigger sensing of nutrients within the hypothalamus. For this purpose, we induced acute hypertriglyceridemia in rats and examined the function of mitochondria in the hypothalamus. Hypertriglyceridemia led to a rapid increase in the mitochondrial respiration in the ventral hypothalamus together with a transient production of ROS. Cerebral inhibition of fatty acids-CoA mitochondrial uptake prevented the hypertriglyceridemia-stimulated ROS production, indicating that ROS derived from mitochondrial metabolism. The hypertriglyceridemia-stimulated ROS production was associated with change in the intracellular redox state without any noxious cytotoxic effects, suggesting that ROS function acutely as signaling molecules. Moreover, cerebral inhibition of hypertriglyceridemia-stimulated ROS production fully abolished the satiety related to the hypertriglyceridemia, suggesting that hypothalamic ROS production was required to restrain food intake during hypertriglyceridemia. Finally, we found that fasting disrupted the hypertriglyceridemia-stimulated ROS production, indicating that the redox mechanism of brain nutrient sensing could be modulated under physiological conditions. Altogether, these findings support the role of mitochondrial ROS as molecular actors implied in brain nutrient sensing. Diabetes 56: 152-160, 2007T he long-term maintenance of the body's energy homeostasis is a complex biological process achieved by numerous complementary mechanisms that imply sensor systems of fuel availability located in both peripheral and central sites. The hypothalamus in the central nervous system is a primary site of integration of nutritional information, which includes neural inputs as well as circulating metabolic signals, i.e., glucose or fatty acids (1,2). In turn, the hypothalamus elicits appropriate behavioral and metabolic responses to counterbalance any changes in the energy status.Previous studies have already shown that an overload of systemic lipids could stimulate activity of specific hypothalamic neurons (3) and modulate expression of neuropeptides, the key effectors of the hypothalamus (3-6), which leads to rapid or more delayed changes in peripheral metabolism. Moreover, chronic elevation of lipids may alter the hepatic sensitivity to insulin through their direct effect on the central nervous system (7). Recent findings (8) indicate that circulating lipids can directly act as signaling molecules, informing the hypothalamus about the body's metabolic status. Accordingly, it has been shown (9) that intracerebroventricular administration of long-chain fatty acids inhibited food intake and stimulated peripheral energy storage.One of the current challenges is to define the way fatty acids control neural activity within the hypotha...

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

“…In recent years, abundant research demonstrates that elevated ROS production causes cellular dysfunction and death, whereas normal ROS levels produced in mitochondria are required as a vital physiological sensor for hypothalamic glucose and fatty acid sensing [31, 32]. The ability of hypothalamic neurons to sense glucose is crucial to maintain body weight and control obesity [33].…”

“…The authors found that the elevated hypothalamic ROS modified the redox state of oxidized and reduced glutathione but failed to cause oxidative stress measured by dichlorofluorescein fluorescence ex vivo . These authors concluded that acute hypertriglyceridemia triggered hypothalamic ROS production due to the increased mitochondrial activity [32]. …”

Hypothalamic dysfunction in obesity

“…Oxidative stress has been reported to precede the appearance of insulin insensitivity in high-fat diet-induced obesity (140) . The induction of hypertryglyceridaemia in rats has been shown to increase mitochondrial respiration in the hypothalamus together with an increase in ROS production (141) . ROS have been shown to be important in both glucose and lipid sensing by the hypothalamus (141,142) and increased ROS in the hypothalamus of the Zucker fatty rat has been linked to abnormal glucose sensing (143) .…”

“…The induction of hypertryglyceridaemia in rats has been shown to increase mitochondrial respiration in the hypothalamus together with an increase in ROS production (141) . ROS have been shown to be important in both glucose and lipid sensing by the hypothalamus (141,142) and increased ROS in the hypothalamus of the Zucker fatty rat has been linked to abnormal glucose sensing (143) . Indeed in the hypothalamus, the regulation of the melanocortin system requires the presence ROS as an acute activator of firing by POMC neurons resulting in decreased food intake, and suppression of ROS leads to activation of the AgRP/NPY neurons and increased feeding.…”

Rôle de la détection centrale des lipides dans le contrôle nerveux de la balance énergétique

“…Ainsi, même si le métabolisme des acides gras peut être nécessaire pour relayer leur effet, on peut aussi envisager des mécanismes d'action indépendants. On peut également signaler l'importance que pourrait jouer les espèces actives de l'oxygène dans la sensibilité centrale aux lipides, comme l'ont montré Benani et al [33]. Il serait également intéressant de parler de ces espèces actives de l'oxygène dans les effets délétères d'un apport excessif de lipides.…”